The Ferret as a Model System for Neocortex Development and Evolution

The neocortex is the largest part of the cerebral cortex and a key structure involved in human behavior and cognition. Comparison of neocortex development across mammals reveals that the proliferative capacity of neural stem and progenitor cells and the length of the neurogenic period are essential for regulating neocortex size and complexity, which in turn are thought to be instrumental for the increased cognitive abilities in humans. The domesticated ferret, Mustela putorius furo, is an important animal model in neurodevelopment for its complex postnatal cortical folding, its long period of forebrain development and its accessibility to genetic manipulation in vivo. Here, we discuss the molecular, cellular, and histological features that make this small gyrencephalic carnivore a suitable animal model to study the physiological and pathological mechanisms for the development of an expanded neocortex. We particularly focus on the mechanisms of neural stem cell proliferation, neuronal differentiation, cortical folding, visual system development, and neurodevelopmental pathologies. We further discuss the technological advances that have enabled the genetic manipulation of the ferret in vivo. Finally, we compare the features of neocortex development in the ferret with those of other model organisms.

Activity-dependent alteration of early myelin ensheathment in a developing sensory circuit

Adaptive myelination has been reported in response to experimental manipulations of neuronal activity, but the links between sensory experience, corresponding neuronal activity, and resultant alterations in myelination require investigation. To study this, we used the Xenopus laevis tadpole, which is a classic model for studies of visual system development and function because it is translucent and visually responsive throughout the formation of this retinotectal system. Here, we report the timecourse of early myelin ensheathment in the Xenopus retinotectal system using immunohistochemistry of myelin basic protein (MBP) along with third-harmonic generation (THG) microscopy, a label-free structural imaging technique. Characterization of the myelination progression revealed an appropriate developmental window to address the effects of early patterned visual experience on myelin ensheathment. To alter patterned activity, we showed tadpoles stroboscopic stimuli and measured the calcium responses of retinal ganglion cell axon terminals. We identified strobe frequencies that elicited robust versus dampened calcium responses, reared animals in these strobe conditions for 7 d, and subsequently observed differences in the amount of early myelin ensheathment at the optic chiasm. This study provides evidence that it is not just the presence but also to the specific temporal properties of sensory stimuli that are important for myelin plasticity.

Retinal ganglion cell interactions shape the developing mammalian visual system

ABSTRACTRetinal ganglion cells (RGCs) serve as a crucial communication channel from the retina to the brain. In the adult, these cells receive input from defined sets of presynaptic partners and communicate with postsynaptic brain regions to convey features of the visual scene. However, in the developing visual system, RGC interactions extend beyond their synaptic partners such that they guide development before the onset of vision. In this Review, we summarize our current understanding of how interactions between RGCs and their environment influence cellular targeting, migration and circuit maturation during visual system development. We describe the roles of RGC subclasses in shaping unique developmental responses within the retina and at central targets. Finally, we highlight the utility of RNA sequencing and genetic tools in uncovering RGC type-specific roles during the development of the visual system.

Selective connectivity limits functional binocularity in the retinogeniculate pathway of the mouse

Eye-specific segregation of retinal ganglion cell (RGC) axons in the dorsal lateral geniculate nucleus (dLGN) is considered a hallmark of visual system development. However, a recent anatomical study showed that nearly half of the neurons in dLGN of adult mice still receive input from both retinae, but functional data about binocularity in mature dLGN is conflicting. Here, we found that a variable but small fraction of thalamocortical neurons is binocular in vivo. Using dual-channel optogenetics in vitro we correspondingly found that dLGN neurons are dominated by retinogeniculate input from one eye only, although most neurons also received small but detectable input from the non-dominant eye. Anatomical overlap between RGC axons and dLGN neuron dendrites did not explain this strong bias towards monocularity. Our data rather suggest that functional input selection and refinement, leaving the remaining non-dominant eye inputs in a juvenile-like state, underlies the prevalent monocularity of neurons in dLGN.

Evolution and development of complex eyes: a celebration of diversity

ABSTRACTFor centuries, the eye has fascinated scientists and philosophers alike, and as a result the visual system has always been at the forefront of integrating cutting-edge technology in research. We are again at a turning point at which technical advances have expanded the range of organisms we can study developmentally and deepened what we can learn. In this new era, we are finally able to understand eye development in animals across the phylogenetic tree. In this Review, we highlight six areas in comparative visual system development that address questions that are important for understanding the developmental basis of evolutionary change. We focus on the opportunities now available to biologists to study the developmental genetics, cell biology and morphogenesis that underlie the incredible variation of visual organs found across the Metazoa. Although decades of important work focused on gene expression has suggested homologies and potential evolutionary relationships between the eyes of diverse animals, it is time for developmental biologists to move away from this reductive approach. We now have the opportunity to celebrate the differences and diversity in visual organs found across animal development, and to learn what it can teach us about the fundamental principles of biological systems and how they are built.

Revisiting the role of Dcc in visual system development with a novel eye clearing method

The Deleted in Colorectal Carcinoma (Dcc) receptor plays a critical role in optic nerve development. Whilst Dcc is expressed postnatally in the eye, its function remains unknown as Dcc knockouts die at birth. To circumvent this drawback, we generated an eye-specific Dcc mutant. To study the organization of the retina and visual projections in these mice, we also established EyeDISCO, a novel tissue clearing protocol that removes melanin allowing 3D imaging of whole eyes and visual pathways. We show that in the absence of Dcc, some ganglion cell axons stalled at the optic disc, whereas others perforated the retina, separating photoreceptors from the retinal pigment epithelium. A subset of visual axons entered the CNS, but these projections are perturbed. Moreover, Dcc-deficient retinas displayed a massive postnatal loss of retinal ganglion cells and a large fraction of photoreceptors. Thus, Dcc is essential for the development and maintenance of the retina.